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Immunologic Research

, Volume 65, Issue 1, pp 402–409 | Cite as

Tolerance, loss of tolerance and regaining tolerance to self by immune-mediated events

  • Arpad Zsigmond Barabas
  • Chad Douglas Cole
  • Richard Milton Graeff
  • Rene Lafreniere
  • Donald Mackay Weir
Mechanism in Autoimmunity

Abstract

Autoimmunity has both beneficial and harmful aspects. Beneficial aspects include: (1) removal of released intracytoplasmic antigens (ags) (cells at the end of their life span or damaged by outside agents) by specific nonpathogenic IgM autoantibodies and mononuclear cells and (2) recognition and elimination of cancerous cells. In contrast, harmful aspects include: (1) mounting a pathogenic autoimmune response against a tissue-derived ag, a ‘modified self,’ resulting in autoimmune disease and (2) inability to recognize and eliminate a cancerous clone. The immune system continuously faces internal and external influences; however, even when it is compromised or overwhelmed, it will still endeavor to regain and maintain tolerance to self. To promote this, we developed a ‘modified vaccination technique’ (MVT) (described as the third vaccination method after active and passive immunizations). It has two components: purified exogenous/endogenous ag (i.e., target ag) and a high-titer-specific antibody (ab) against the target ag made into an immune complex (IC) with predetermined immune-inducing components. The MVT works by ab information transfer (production of same class of immunoglobulin with the same specificity against the target ag that is present in the vaccine), thereby re-establishing tolerance to self (caused by exogenous/endogenous ags) following repeated administration of appropriate ICs. This vaccination technique can be used both prophylactically and therapeutically, and it mimics the immune system’s natural abilities to respond to corrective information specifically, rapidly, safely and with minimal side effects and makes this approach a novel solution for many disorders that are difficult or impossible to cure or manage.

Keywords

Tolerance Modified vaccination technique Immune complex Autoantibody 

Abbreviations

aab

Autoantibody

aag

Autoantigen

ab

Antibody

ag

Antigen

BB

Brush border

HN

Heymann nephritis

IC

Immune complex

MM

Multiple myeloma

MVT

Modified vaccination technique

rKF3

Rat kidney fraction 3

rarKF3

Rat anti-rat kidney fraction 3

Notes

Acknowledgments

This work was supported by a Grant from an anonymous donor. All authors have contributed to, critically reviewed and approved this article. None of the authors has any conflict of interest to declare. We acknowledge the assistance of our research associate, Zoltan Kovacs, in computer and laboratory-related work.

References

  1. 1.
    Weir DM, Pinckard RN, Elson CJ, Suckling DE. Naturally occurring anti-tissue antibodies in rat sera. Clin Exp Immunol. 1966;1(4):433–42.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Weir DM, Elson CJ. Antitissue antibodies and immunological tolerance to self. Arthritis Rheum. 1969;12(3):254–60.CrossRefPubMedGoogle Scholar
  3. 3.
    Weir DM, Pinckard RN. Failure to induce tolerance to rat tissue antigens. Immunology. 1967;13(4):373–80.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Weir DM. The immune response after tissue injury. Pathol Eur. 1966;1(1):108–18.PubMedGoogle Scholar
  5. 5.
    Barabas AZ, Cole CD, Barabas AD, Lafreniere R. Production of a new model of slowly progressive Heymann nephritis. Int J Exp Pathol. 2003;84(6):245–58.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Barabas AZ, Cole CD, Barabas AD, Lafreniere R. Production of Heymann nephritis by a chemically modified renal antigen. Int J Exp Pathol. 2004;85(5):277–85.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Rich MW. Drug-induced lupus. The list of culprits grows. Postgrad Med. 1996;100(3):299–308.CrossRefPubMedGoogle Scholar
  8. 8.
    Soldan SS, Jacobson S. Infection and multiple sclerosis. In: Shoenfeld Y, Rosenzweig LJ, editors. Infection and autoimmunity. Amsterdam: Elsevier; 2004. p. 559–82.CrossRefGoogle Scholar
  9. 9.
    Totoritis MC, Rubin RL. Drug-induced lupus. Genetic, clinical, and laboratory features. Postgrad Med. 1985;78(3):149–61.CrossRefPubMedGoogle Scholar
  10. 10.
    Wucherpfennig KW. Mechanisms for the induction of autoimmunity by infectious agents. J Clin Invest. 2001;108(8):1097–104.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Yung RL, Richardson BC. Drug-induced lupus. Rheum Dis Clin N Am. 1994;20(1):61–86.Google Scholar
  12. 12.
    Boes M, Schmidt T, Linkemann K, Beaudette BC, Marshak-Rothstein A, Chen J. Accelerated development of IgG autoantibodies and autoimmune disease in the absence of secreted IgM. Proc Natl Acad Sci USA. 2000;97(3):1184–9.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Quartier P, Potter PK, Ehrenstein MR, Walport MJ, Botto M. Predominant role of IgM-dependent activation of the classical pathway in the clearance of dying cells by murine bone marrow-derived macrophages in vitro. Eur J Immunol. 2005;35(1):252–60.CrossRefPubMedGoogle Scholar
  14. 14.
    Wermeling F, Karlsson MC, McGaha TL. An anatomical view on macrophages in tolerance. Autoimmun Rev. 2009;9(1):49–52.CrossRefPubMedGoogle Scholar
  15. 15.
    Manson JJ, Mauri C, Ehrenstein MR. Natural serum IgM maintains immunological homeostasis and prevents autoimmunity. Springer Semin Immunopathol. 2005;26(4):425–32.CrossRefPubMedGoogle Scholar
  16. 16.
    Ogden CA, Kowalewski R, Peng Y, Montenegro V, Elkon KB. IgM is required for efficient complement mediated phagocytosis of apoptotic cells in vivo. Autoimmunity. 2005;38(4):259–64.CrossRefPubMedGoogle Scholar
  17. 17.
    Avrameas S. Natural autoantibodies: from ‘horror autotoxicus’ to ‘gnothi seauton’. Immunol Today. 1991;12(5):154–9.PubMedGoogle Scholar
  18. 18.
    Zwart B, Ciurana C, Rensink I, Manoe R, Hack CE, Aarden LA. Complement activation by apoptotic cells occurs predominantly via IgM and is limited to late apoptotic (secondary necrotic) cells. Autoimmunity. 2004;37(2):95–102.CrossRefPubMedGoogle Scholar
  19. 19.
    Blank M, Shoenfeld Y. B cell targeted therapy in autoimmunity. J Autoimmun. 2007;28(2–3):62–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Byrd JC, Waselenko JK, Maneatis TJ, Murphy T, Ward FT, Monahan BP, et al. Rituximab therapy in hematologic malignancy patients with circulating blood tumor cells: association with increased infusion-related side effects and rapid blood tumor clearance. J Clin Oncol. 1999;17(3):791–5.CrossRefPubMedGoogle Scholar
  21. 21.
    Dorner T, Radbruch A, Burmester GR. B-cell-directed therapies for autoimmune disease. Nat Rev Rheumatol. 2009;5(8):433–41.CrossRefPubMedGoogle Scholar
  22. 22.
    Mok CC. Rituximab for the treatment of rheumatoid arthritis: an update. Drug Des Devel Ther. 2014;8:87–100.Google Scholar
  23. 23.
    Perosa F, Favoino E, Caragnano MA, Prete M, Dammacco F. CD20: a target antigen for immunotherapy of autoimmune diseases. Autoimmun Rev. 2005;4(8):526–31.CrossRefPubMedGoogle Scholar
  24. 24.
    Rommer PS, Dudesek A, Stuve O, Zettl UK. Monoclonal antibodies in treatment of multiple sclerosis. Clin Exp Immunol. 2014;175(3):373–84.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Townsend MJ, Monroe JG, Chan AC. B-cell targeted therapies in human autoimmune diseases: an updated perspective. Immunol Rev. 2010;237(1):264–83.CrossRefPubMedGoogle Scholar
  26. 26.
    Barabas AZ, Cole CD, Barabas AD, Lafreniere R. Down-regulation of pathogenic autoantibody response in a slowly progressive Heymann nephritis kidney disease model. Int J Exp Pathol. 2004;85(6):321–34.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Barabas AZ, Lafreniere R. Antigen-specific down-regulation of immunopathological events in an experimental autoimmune kidney disease. Autoimmun Rev. 2005;4(8):565–70.CrossRefPubMedGoogle Scholar
  28. 28.
    Barabas AZ, Cole CD, Lafreniere R, Weir DM. Regaining tolerance to a self-antigen by the modified vaccination technique. Clin Rev Allergy Immunol. 2013;45(2):193–201.CrossRefPubMedGoogle Scholar
  29. 29.
    Borchers AT, Naguwa SM, Keen CL, Gershwin ME. The implications of autoimmunity and pregnancy. J Autoimmun. 2010;34(3):J287–99.CrossRefPubMedGoogle Scholar
  30. 30.
    Barabas AZ, Cole CD, Barabas AD, Bahlis NJ, Lafreniere R. A vaccination technique to combat presently untreatable chronic ailments. Bioprocess J. 2007;6(4):12–8.CrossRefGoogle Scholar
  31. 31.
    Barabas AZ, Cole CD, Barabas AD, Graeff RM, Lafreniere R, Weir DM. Modified vaccination technique for prophylactic and therapeutic applications to combat endogenous antigen-induced disorders. Scand J Immunol. 2010;71(3):125–33.CrossRefPubMedGoogle Scholar
  32. 32.
    Feldmann M, Steinman L. Design of effective immunotherapy for human autoimmunity. Nature. 2005;435(7042):612–9.CrossRefPubMedGoogle Scholar
  33. 33.
    Hogan SL, Muller KE, Jennette JC, Falk RJ. A review of therapeutic studies of idiopathic membranous glomerulopathy. Am J Kidney Dis. 1995;25(6):862–75.CrossRefPubMedGoogle Scholar
  34. 34.
    Pani A. Standard immunosuppressive therapy of immune-mediated glomerular diseases. Autoimmun Rev. 2013;12(8):848–53.CrossRefPubMedGoogle Scholar
  35. 35.
    Perna A, Schieppati A, Zamora J, Giuliano GA, Braun N, Remuzzi G. Immunosuppressive treatment for idiopathic membranous nephropathy: a systematic review. Am J Kidney Dis. 2004;44(3):385–401.CrossRefPubMedGoogle Scholar
  36. 36.
    Barabas AZ, Cole CD, Kovacs ZB, Lafreniere R. Elevated antibody response by antigen presentation in immune complexes. Med Sci Monit. 2007;13(5):BR119–24.PubMedGoogle Scholar
  37. 37.
    Barabas AZ, Weir DM, Cole CD, Barabas AD, Bahlis NJ, Graeff RM, et al. Preventing and treating chronic disorders using the modified vaccination technique. Front Biosci. 2009;14:3892–8.CrossRefGoogle Scholar
  38. 38.
    Barabas AZ, Cole CD, Sensen M, Lafreniere R. Production of heterologous IgG antibody against Heymann nephritis antigen by injections of immune complexes. Int J Exp Pathol. 2012;93(1):11–7.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Mackay IR. Travels and travails of autoimmunity: a historical journey from discovery to rediscovery. Autoimmun Rev. 2010;9(5):A251–8.CrossRefPubMedGoogle Scholar
  40. 40.
    Selmi C. Autoimmunity in 2012. Clin Rev Allergy Immunol. 2013;45(2):290–301.CrossRefPubMedGoogle Scholar
  41. 41.
    Sioud M. Does our current understanding of immune tolerance, autoimmunity, and immunosuppressive mechanisms facilitate the design of efficient cancer vaccines? Scand J Immunol. 2009;70(6):516–25.CrossRefPubMedGoogle Scholar
  42. 42.
    Barabas AZ, Cole CD, Barabas AD, Graeff RM, Lafreniere R, Weir DM. Correcting autoimmune anomalies in autoimmune disorders by immunological means, employing the modified vaccination technique. Autoimmun Rev. 2009;8(7):552–7.CrossRefPubMedGoogle Scholar
  43. 43.
    Nahta R, Esteva FJ. Trastuzumab: triumphs and tribulations. Oncogene. 2007;26(25):3637–43.CrossRefPubMedGoogle Scholar
  44. 44.
    Heymann W, Hackel DB, Harwood S, Wilson SG, Hunter JLP. Production of nephritic syndrome in rats by Freund’s adjuvant and rat kidney suspensions. Proc Soc Exp Biol Med. 1959;100:660–4.CrossRefPubMedGoogle Scholar
  45. 45.
    Barabas AZ, Cole CD, Barabas AD, Cowan JM, Yoon CS, Waisman DM, et al. Presence of immunoglobulin M antibodies around the glomerular capillaries and in the mesangium of normal and passive Heymann nephritis rats. Int J Exp Pathol. 2004;85(4):201–12.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Barabas AZ, Cole CD, Lafreniere R, Weir DM. Implicated autoantibodies in a kidney disease. In: Jenkins GE, Hall JI, editors. Autoantibodies: detection, pathogenicity and health implications. Hauppauge: Nova Science Publishers, Inc; 2012. p. 1–36.Google Scholar
  47. 47.
    Andres G, Brentjens JR, Caldwell PR, Camussi G, Matsuo S. Formation of immune deposits and disease. Lab Invest. 1986;55(5):510–20.PubMedGoogle Scholar
  48. 48.
    Cameron JS. Membranous nephropathy–still a treatment dilemma. N Engl J Med. 1992;327(9):638–9.CrossRefPubMedGoogle Scholar
  49. 49.
    Ronco P, Debiec H. Molecular dissection of target antigens and nephritogenic antibodies in membranous nephropathy: towards epitope-driven therapies. J Am Soc Nephrol. 2006;17(7):1772–4.CrossRefPubMedGoogle Scholar
  50. 50.
    Barabas AZ, Cole CD, Barabas AD, Lafreniere R. Downregulation of a pathogenic autoantibody response by IgM autoantibodies directed against the nephritogenic antigen in slowly progressive Heymann nephritis. Pathol Int. 2006;56(4):181–90.CrossRefPubMedGoogle Scholar
  51. 51.
    Jaini R, Kesaraju P, Johnson JM, Altuntas CZ, Jane-Wit D, Tuohy VK. An autoimmune-mediated strategy for prophylactic breast cancer vaccination. Nat Med. 2010;16(7):799–803.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    von Karsa L, Arbyn M, De Vuyst H, Dillner J, Dillner L, Franceschi S, et al. European guidelines for quality assurance in cervical cancer screening. Summary of the supplements on HPV screening and vaccination. Papillomavirus Res. 2015;1:22–31.CrossRefGoogle Scholar
  53. 53.
    Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol. 1999;17(9):2639–48.CrossRefPubMedGoogle Scholar
  54. 54.
    Kabe KL, Kolesar JM. Role of trastuzumab in adjuvant therapy for locally invasive breast cancer. Am J Health Syst Pharm. 2006;63(6):527–33.CrossRefPubMedGoogle Scholar
  55. 55.
    Munshi C, Aarhus R, Graeff R, Walseth TF, Levitt D, Lee HC. Identification of the enzymatic active site of CD38 by site-directed mutagenesis. J Biol Chem. 2000;275(28):21566–71.CrossRefPubMedGoogle Scholar
  56. 56.
    Munshi CB, Fryxell KB, Lee HC, Branton WD. Large-scale production of human CD38 in yeast by fermentation. Methods Enzymol. 1997;280:318–30.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Arpad Zsigmond Barabas
    • 1
  • Chad Douglas Cole
    • 2
  • Richard Milton Graeff
    • 3
  • Rene Lafreniere
    • 1
  • Donald Mackay Weir
    • 4
  1. 1.Department of Surgery, 2808 Health Sciences CentreUniversity of CalgaryCalgaryCanada
  2. 2.Department of NeurosurgeryUniversity of UtahSalt Lake CityUSA
  3. 3.Department of PharmacologyUniversity of MinnesotaMinneapolisUSA
  4. 4.University of Edinburgh Medical SchoolEdinburghScotland, UK

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